Human smoking appears to be influenced in part by genetic factors. Genotype may influence who does or does not smoke and may influence the course and severity of withdrawal responses observed when smoking is terminated. Similarly, genetic factors are important in the regulation of the responses of mice to either acute or chronic nicotine exposure. as well as in the expression of brain receptors which may regulate the responses to nicotine. The studies outlined in this proposal will examine the role of genotype in the regulation of nicotine effects on acute sensitivity, tolerance development and withdrawal. Simultaneously the genetic regulation of putative nicotinic receptor levels, the changes in these levels during treatment and after withdrawal will be investigated. Six inbred strains that differ in response to nicotine and expression of putative nicotinic receptors will be used as parental stocks for both diallel crosses land classical genetic crosses. The parental strains and their crosses will be used to study the influence of genetic factors on: 1) regulation of the acute responses to nicotine and regulation of the expression of nicotinic binding sites, their subtypes and function with the goal of determining the relationship between acute responsiveness and receptors; 2) regulation of tolerance development and changes in the expression of nicotinic receptor number and function with chronic nicotine treatment with the goal of understanding the biochemical basis for the development of itolerance to nicotine; 3) expression of a withdrawal syndrome and the relationship between the extent of tolerance development, the magnitude of receptor changes, and !the severity of the withdrawal; and 4) control of tolerance development after the exposure to nicotinic agents other than nicotine itself. The results obtained in this study should be valuable in establishing an animal model for nicotine tolerance and dependence with an emphasis on the role of genotype in regulating the physiological and biochemical factors that control nicotine responsiveness.